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Phase 2a Baxdrostat Data Show Promise for Primary Aldosteronism

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Treatment with baxdrostat resolved or reduced the severity of hypertension, excessive aldosterone production, and hypokalemia in the phase 2a SPARK trial.

New data from the phase 2a SPARK trial suggest baxdrostat, a highly selective, second-generation, nonimidazole aldosterone synthase inhibitor, may offer a promising treatment option for patients with primary aldosteronism.1

“Recommended therapies for primary aldosteronism have changed little over the past several decades and are completely effective in only a minority of patients,” Morris Brown, MD, FRCP, FMedSci, FRS, a professor of endocrine hypertension at Queen Mary University and clinical pharmacologist at Barts Health NHS Trust, and colleagues wrote, citing the potential advantages of selective aldosterone synthase inhibitors over other existing drugs and their ability to target the root cause of primary aldosteronism.1

While 2 first-generation aldosterone synthase inhibitors were previously studied over 4 or 8 weeks in patients with primary aldosteronism and led to modest reductions in blood pressure, these findings were attributed to elevations in the plasma 11-deoxycorticosterone level, and neither drug has advanced into a pivotal trial for the treatment of primary aldosteronism. To date, spironolactone remains the only licensed therapy.1,2

A multicenter, open-label, prospective study of baxdrostat, a highly selective, second-generation, nonimidazole aldosterone synthase inhibitor, SPARK enrolled patients with hypertension and primary aldosteronism diagnosed according to the Endocrine Society guidelines. Participants started treatment with baxdrostat at a dose of 2 mg per day for the first 4 weeks; the dose was then increased monthly to 4 or 8 mg per day on the basis of the blood-pressure measurement and the absence of unacceptable adverse events.1

The primary endpoints were change in systolic blood pressure from baseline to week 12 and safety. Patients were offered the opportunity to continue into an active extension period from week 12 through week 72.1

A total of 15 patients with a mean systolic blood pressure of 151.5±13.5 and diastolic blood pressure of 90.3±8.8 mm Hg were enrolled and completed part 1 of the study. At week 12, results showed systolic blood pressure was reduced in all 15 patients by a mean of 24.9 mm Hg (95% confidence interval [CI], 19.0 to 30.8). Hypokalemia was corrected in all 5 patients who had the condition, and no serious adverse events occurred during part 1 of the study.1

At week 12, diastolic blood pressure decreased by a mean 10.6±9.0 mm Hg. The blood-pressure target, <140/90 mm Hg, was reached in 11 of the 15 patients (73%; 95% CI, 45 to 92). Investigators noted the plasma aldosterone-to-renin ratio was substantially reduced in all the patients by a median of 97.3% (interquartile range, 84.3 to 98.9), and the target aldosterone–renin ratio (<15, with aldosterone measured in nanograms per deciliter and renin in nanograms per milliliter per hour) was reached in 14 of the 15 patients (93%; 95% CI, 68 to 100).1

Further analysis revealed plasma and 24-hour urinary aldosterone levels decreased by 90.9% (95% CI, 73.9 to 92.9) and 91.6% (95% CI, 89.6 to 94.3), respectively, at week 12. Investigators pointed out the reciprocal rise in plasma renin activity was more gradual, with an increase by a factor of 1.8 (95% CI, 0.5 to 8.5) at week 12 and an increase by a factor of 6.0 (95% CI, 2.0 to 16.3) at week 72.1

In contrast, they noted the serum 11-deoxycorticosterone level peaked early, with an increase by a factor of 11.5 (95% CI, 6.2 to 16.9) at week 8; the level then decreased by approximately 50% by week 36. The mean plasma cortisol level was 7.0±3.1 μg per deciliter at baseline and 9.3±3.8 μg per deciliter at week 12.1

A total of 14 patients continued into part 2 of the study, 4 of whom received the 8-mg dose of baxdrostat and discontinued the treatment before 72 weeks.1

While investigators acknowledged the lack of a placebo-control group precluded precise quantification of the effects of baxdrostat, they noted the reductions in systolic blood pressure of 25 mm Hg are rare. Additionally, they pointed out the median 97% reduction in the aldosterone–renin ratio exceeded the reductions observed after surgical removal of a culprit adrenal gland and note initial, marked increases in the 11-deoxycorticosterone level may exceed protein-binding capacity and delay maximal mineralocorticoid inhibition.1

Furthermore, investigators describe the subsequent decline in 11-deoxycorticosterone and persistent aldosterone suppression after baxdrostat withdrawal as predicted consequences of a maladaptive response to salt, which has been hypothesized to be involved in the pathogenesis and reversal of primary aldosteronism.1

“In our study involving 15 patients with primary aldosteronism, treatment with baxdrostat resolved or reduced the severity of hypertension, excessive aldosterone production, and hypokalemia,” investigators concluded.1

References
  1. Turcu AF, Freeman MW, Bancos I, et al. Phase 2a Study of Baxdrostat in Primary Aldosteronism. The New England Journal of Medicine. doi:10.1056/NEJMc2508629
  2. Primary Aldosteronism Foundation. How is PA Treated? Accessed July 14, 2025. https://primaryaldosteronism.org/medical-option/

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